Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus

Michiyo Tomita, Brita J. Holman, Lee S. Williams, Kevin C.H. Pang, Thomas J. Santoro

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-γ (IFN-γ) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-Iβ and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-α were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFN-γ, IL-Iβ, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.

Original languageEnglish (US)
Pages (from-to)26-33
Number of pages8
JournalJournal of Neuroscience Research
Volume64
Issue number1
DOIs
StatePublished - Apr 1 2001

Keywords

  • Cerebellum
  • Cytokines
  • Gene expression
  • MRL-lpr/lpr mice
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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